Diabetes Mellitus- Its complications, factors influencing ...

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Journal of Chemical and Pharmaceutical Research __________________________________________________

J. Chem. Pharm. Res., 2010, 2(6):7-25 ISSN No: 0975-7384 CODEN(USA): JCPRC5

Diabetes Mellitus- Its complications, factors influencing complications and prevention- An Overview S. Rambhade1, A. K. Chakraborty1*, U. K. Patil1, A. Rambhade2 1

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, People’s Institute of Pharmacy & Research Centre, People’s Group, Bhopal, M.P., India 2 Department of Pharmacology, Faculty of Pharmacy, Sagar Institute of Research Technology and Science, Bhopal, M.P., India

__________________________________________________________________ ABSTRACT This review aims to summarize the major advances of the preceding year and to put them in to the context of current opinion on diabetes mellitus. Despite the advent of life-prolonging insulin for the treatment of diabetes, the appearance and progression of many of the disabling complications associated with this disease cannot be prevented through the administration of insulin. Clinically, the onset and rate of progression of diabetic complications, including cataract, corneal epitheliopathy, microangiopathy, nephropathy, neuropathy, and retinopathy, appear to be dependent upon both the duration and the severity of the diabetes. This review summarizes the specific pathogenic mechanisms of microvascular complications for which clinical therapies have been developed, including the polyol pathway, advanced glycation end products, protein kinase c, vascular epithelium growth factor, and the superoxide pathway. The review further focuses on therapies for these targets that are currently available or are undergoing late-stage clinical trials. Key words: Diabetes, Diabetic complications, Polyol pathway, Oxidative stress, Protein kinase c.

_____________________________________________________________________________ INTRODUCTION Diabetes has been a mass killer on globe for quite a long time now. There have been several previous estimates of the number of persons with diabetes. The World Health Organization (WHO) published estimates for the years 2000 and 2030, using data from 40 countries but 7

A. K. Chakraborty et al J. Chem. Pharm. Res., 2010, 2(6):7-25 ______________________________________________________________________________ extrapolated to the 191 WHO member states[1]. WHO estimates that more than 180 million people worldwide have diabetes, this number is likely to more than double by 2030[2]. J.E. Shaw et al, estimates suggest that in 2010 there are 285 million people worldwide with diabetes, with considerable disparity between populations and regions. The study estimate for 2010 of 285 million adults with diabetes is 67% higher than the 2004 published estimate for the year 2000[3], and J.E. Shaw et al, 2030 estimate of 439 million is 20% higher than the same study’s estimate for 2030. In 2005, an estimated 1.1 million people died from diabetes. Almost 80% of diabetes deaths occur in low and middle income countries. WHO projects that diabetes death will increase by more than 50% in the next 10 year without urgent action. The global increase in diabetes will occur because of population ageing and growth and because of increasing trends towards obesity, unhealthy diets and sedentary lifestyles[4]. In developed countries most people with diabetes are above the age of retirement, whereas in developing countries those most frequently affected are aged between 35 and 64. Chronic diabetic complications constitute a group of diseases responsible for substantial morbidity and mortality, and prevention of such complications is a key issue in the management of the diabetes epidemic[5-7]. Therapeutic modalities for diabetes have evolved a great deal. However, most people with this disorder go on to develop complications leading to damage to various body tissues. These complications include diabetic retinopathy, nephropathy, neuropathy, cardiomyopathy, and macroangiopathic complications such as atherosclerosis[8,9]. The macrovascular complications are not diabetes specific but are more pronounced in diabetes. Diabetic complications arise primarily because of hyperglycemia-induced metabolic changes leading to changes in the structural and functional properties of macromolecules[10,11]. Frequency of complications Among people with diabetes, about 15% have type 1 (formerly known as insulin-dependent diabetes); while about 85% have type 2 diabetes (formerly known as non insulin-dependent diabetes). In type 1, there is β cells are detectable in blood, but some are idiopathic (type 1B)-no β cell antibody is found. In all type 1 cases circulating insulin levels are low or very low, and patients are more prone to ketosis. This type is less common and has a low degree of genetic predisposition. In type 2 diabetes, a moderate reduction in the β cell mass has been reported, though in some cases reduction in β cell mass was not observed[12,13]. In contrast, type 2 diabetes is usually part of the "metabolic syndrome" which is associated with other risk factor from early in the disease process, including abdominal obesity, hypertension, dyslipidaemia, prothrombotic state and insulin resistance[14]. Macrovascular disease is a major cause of morbidity and mortality in type 2 diabetes; microvascular complications are often present when diabetes is diagnosed, even in people with no symptoms[15-18]. Clinical complications of diabetes mellitus Retinopathy Diabetes Mellitus (DM) is a major cause of avoidable blindness in both the developing and the developed countries. After 15 years of diabetes, approximately 2% of people become blind and about 10% develop severe visual impairment[2]. Patients with diabetic retinopathy (DR) are 25 times more likely to become blind than non-diabetics[19]. Good glycemic control arrests the development and progression of DR and decreases the visual loss[20]. Technological advances 8

A. K. Chakraborty et al J. Chem. Pharm. Res., 2010, 2(6):7-25 ______________________________________________________________________________ have improved the diagnostic accuracy of screening methods and access of the diabetic patients to the specialist care. In the last three decades, the treatment strategies have been revised to include, early surgical interventions and pharmacotherapies, besides laser photocoagulation[2123]. Diabetic retinopathy is classified in various progressive stages, namely, Nonproliferative (background) retinopathy, Preproliferative (severe or advanced background) retinopathy, and Proliferative retinopathy. The retina is comprised of several tissue types, including neural tissue with respective support cells and vascular tissue[24]. Diabetic retinopathy predominantly affects the vascular components of the retina. Pathological changes in background diabetic retinopathy include capillary basement membrane thickening, pericyte loss, microaneurysms, acellular capillaries, increased capillary permeability with exudate deposits, and retinal microinfarcts[25]. In advanced proliferative retinopathy, neovascularization develops with its devastating consequences. The final metabolic pathway causing DR is unknown. There are several theories. Electrolytic imbalance caused by the high aldose reductase levels leads to cell death, especially retinal pericytes, which cause microaneurysm formation[26]. Apart from this, thickening of the capillary basement membrane and increased deposition of extracellular matrix components contribute to the development of abnormal retinal hemodynamics[27]. In diffuse type of diabetic macular edema (DME), breakdown of the inner blood- retinal barrier results in accumulation of extracellular fluid. Increased retinal leukostasis has been reported and it causes capillary occlusions and dropout, non-perfusion, endothelial cell damage and vascular leakage due to its less deformable nature. Currently, there has been a great interest in vasoproliferative factors, which induce neovascularization. It has been shown that retinal ischemia stimulates a pathologic neovascularization mediated by angiogenic factors, such as vascular endothelial growth factor (VEGF), which results in proliferative diabetic retinopathy (PDR)[28,29]. VEGFs are released by retinal pigment epithelium, pericytes and endothelial cells of the retina[30]. Nephropathy Diabetes is among leading causes of kidney failure. 10-20% of people with diabetes die of kidney failure[2]. Diabetic nephropathy affects approximately 30% of type 1 diabetic patients. Diabetes remains the most important cause of renal failure in industrialized countries[31-33]. Type II diabetes and diabetic nephropathy are clearly chronic progressive diseases that are associated with a combination of genetic, lifestyle and environmental factors[34]. While many risk factors have been identified, such as obesity, diet and other lifestyle factors, it is highly likely that there are as yet unidentified environmental factors that influence whether or not an individual will become diabetic, or whether mild or incipient diabetes progresses to a more advanced disease state[35-37]. Glomerular hyperfiltration leading to microalbuminuria is the earliest clinical marker of this disease. With progression of renal damage, patients develop microalbuminuria and reduced glomerular filtration rate[38,39]. Pathological features of diabetic nephropathy include mesangial matrix expansion, thickening of glomerular capillary basement membrane, and tubulointerstitial fibrosis[40]. In earlier stages, however, there is renal enlargement due to cellular hypertrophy 9

A. K. Chakraborty et al J. Chem. Pharm. Res., 2010, 2(6):7-25 ______________________________________________________________________________ affecting both the glomeruli and tubules. Eventually, the glomerular filtration rates continue to decline and the patients develop arteriolosclerosis and glomerulosclerosis with obliteration of the filtration area due to increased production and decreased degradation of extracellular matrix (ECM) proteins. In the later stages, patients develop characteristic nodular accumulation of extracellular matrix proteins, that is, Kimmelstiel–Wilson nodules[41]. Clinically, overt nephropathy manifests as proteinuria in the nephritic range, hypertension, and other features of renal failure[42]. It has been demonstrated that, similar to other chronic complications, a high blood glucose level is the initiating factor leading to the development of renal damage in diabetes[43,44]. Furthermore, it has been demonstrated that good glucose control may even reverse the structural changes in the kidneys. Identification of patients at high risk by screening for microalbuminuria now occurs in many hospital clinics and potentially early and effective anti-hypertensive treatment in these patients can postpone or prevent clinical nephropathy. Blockade of the reninangiotensin system by angiotensin I converting enzyme inhibitors may decrease microalbuminuria in normotensive diabetic patients independently of the fall in blood pressure[45]. Neuropathy According to WHO, Diabetic neuropathy is damage to the nerves as a result of diabetes and affects up to 50% of people with diabetes Neuropathic pain can be described as a sensation of paresthesia, numbness, and burning that is caused by the sustained, abnormal processing of CNS neuronal input. Both the somatic and autonomic nervous system can be affected by diabetes, causing a variety of symptoms[46,47]. At the severe end of the spectrum, diabetic nerve disease is a major cause of lower extremity amputation[48]. It has been reported that, Inflammation is more clearly involved in the specific inflammatory neuropathies such as vasculitic and granulomatous disease than in diabetic neuropathy [49], though it has not been studied in age related neuropathies. P and E-selectin, activated during the inflammatory process, predict the decline in peripheral nerve function among diabetic patients. Impaired blood flow and endoneurial microvasculopathy, mainly thickening of the blood vessel wall or occlusion, play a critical role in the pathogenesis of diabetic neuropathy. Metabolic disturbances in the presence of an underlying genetic predisposition, cause reduce nerve perfusion[50]. Oxidative stress-related mechanisms are also important in vascular dysfunction, and tend to increase vasoconstriction[51]. Sensory and local autonomic nerve function deficits appear to predominate in patients with critical limb ischemia. Improving blood flow to tissues may improve nerve conduction velocity in diabetic neuropathy[52]. Oxidative and nitrosative stress and inflammation are implicated in several neurodegenerative disorders including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). It is greater in diabetic patients prior to development of peripheral neuropathy and particularly in those with peripheral neuropathy [53]. Retrospective and prospective studies have suggested a relationship between hyperglycemia and the development and severity of diabetic neuropathy, and significant effects of intensive insulin treatment on prevention of neuropathy [54].

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A. K. Chakraborty et al J. Chem. Pharm. Res., 2010, 2(6):7-25 ______________________________________________________________________________ To date, pharmacologic agents used in the treatment of diabetic neuropathy are used empirically to address symptoms are Low-dose tricyclic antidepressants, anticonvulsants (gabapentin, pregabalin, carbamazepine, and potentially phenytoin), serotonin-norepinephrine reuptake inhibitors (duloxetine, venlefaxine), topical analgesic (topical capsaicin), and various oral pain medications are agents that are currently available [55,56]. Cardiomyopathy Diabetes increases the risk of heart disease and stroke and nearly 50% of people with diabetes die of cardiovascular disease. Cerebrovascular disease (CeVD) represents a major cause of morbidity and mortality worldwide. The more overweight an individual is, the more likely he or she will be insulin resistant and will face an increased risk for developing all the associated abnormalities such as hypertension, type 2 diabetes mellitus (DM), and cardiovascular disease, including stroke [57,58]. DM, hypertension, smoking, dyslipidemia, atrial fibrillation (AF), and physical inactivity are important risk factors for stroke, and their management with lifestyle modifications and pharmacological treatment can reduce stroke-associated morbidity and mortality in the general population [59,60]. Diabetic cardiomyopathy can act as an independent factor affecting the cardiac structure and function and may also modulate prognosis of other complications such as ischemic heart disease [61]. It was demonstrated that diabetic patients had larger mean diameters of ventricular myocardial cells and higher percentage of interstitial fibrosis than control subjects[62].Morphological changes in diabetic cardiomyopathy include myocyte hypertrophy and/or necrosis, interstitial and perivascular fibrosis, and capillary basement membrane thickening [63]. Functional abnormalities involve both the systolic and diastolic properties of the myocardium, such as impaired relaxation, reduced compliance with elevated end-diastolic pressure, cardiac hypertrophy, and chamber dilatation [64]. The overall relative risk of stroke is 1.5 to 3 times greater in patients with DM [65-67], while the relative risk for stroke is 10 times higher in diabetic patients younger than 55 [68]. Recurrent stroke is also twice more frequent in diabetic patients [69]. More importantly, both short and long-term mortality after stroke are significantly greater in diabetic patients [70]. Overall, the outcome of CeVD in patients with DM is worse than in nondiabetic patients. The principal mechanisms by which DM can lead to microvascular damage and finally CeVD are the following: Increased production of free oxygen radicals and oxidative stress [71]. Increased production of glycosylated products [72]. Increased activity of aldose reductase in the polyol pathway, leading to intracellular accumulation of sorbitol and fructose [71]. Activation of specific protein kinase C (PKC) isoforms [73,74]. Formation of reactive oxygen species due to hyperglycemia and insulin resistance leads to cell damage [75]. Free oxygen radicals decrease the bioavailability of endothelium-derived nitric oxide resulting in vasoconstriction, platelet activation, and smooth muscle cell proliferation. Activation of specific isoforms, especially PKC β and PKC δ, leads to cell proliferation,

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A. K. Chakraborty et al J. Chem. Pharm. Res., 2010, 2(6):7-25 ______________________________________________________________________________ impaired glucose and lipid metabolism, expression of atherosclerosis-promoting genes, decreased vasodilation, and increased vascular permeability. Proposed guidelines for the early management of hyperglycemia during ischemic stroke [76] are as follows: Initiate insulin therapy when plasma glucose is >140-180 mg/dl. Therapeutic target: plasma glucose 80-140 mg/dl. The recommendations on acute stroke are the following: Critically ill patients: plasma glucose close to 110 mg/dl and always